Boosted Protease Inhibitors. Current and Future Role in HIV Therapy.2014

Boosted Protease Inhibitors: Current and Future Role in HIV Therapy

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Faculty and Disclosure Information

Sally Hodder, MDProfessor of Medicine Rutgers, New Jersey Medical SchoolNewark, New Jersey

Sally Hodder, MD, has disclosed that she has received consulting fees from Bristol-Myers Squibb, Gilead Sciences, Janssen, and Merck; has received funds for research support from Bristol-Myers Squibb, Gilead Sciences, Janssen, and ViiV; and her spouse has ownership interest in Merck.

Boosted Protease Inhibitors: Current and Future Role in HIV Therapy

Boosted Regimens: An Introduction


60,000

AIDS-Related Mortality and Advent of PIs

Introduction of PI-containing triple ART

80,000

70,000

50,000

40,000

30,000

20,000

10,000

0

Dea

ths

(n)

Yr of Death

19

85

19

86

19

87

19

88

19

89

19

90

19

91

19

92

19

93

19

94

19

95

19

96

19

97

19

98

19

99

20

00

20

01

20

02

20

03

20

04

20

05

20

06

20

07

20

08

20

09

20

10

CDC.gov. Epidemiology of HIV infection.


Milestones in the Evolution of the PI Class

PAST PRESENT(Not-too-distant)

FUTURE

Many pills per day Multiple doses necessary

Improved tolerabilitySome boosted

1 pill per day (+ RTV & NRTIs)Boosting gold standard

Manageable toxicity

More coformulations Single-tablet regimens

High toxicity

Once-daily dosingCoformulation

Some treatment-limiting toxicity

SQVRTVIDV

APVNFV

FPV/RTVLPV/RTV

ATVATV/RTVDRV/RTV

ATV/COBIDRV/COBI

DRV/COBI/TAF/FTC

SQV/RTVIDV/RTV


Ritonavir-Boosted PIs

PIs traditionally coupled with RTV (100-400 mg QD) as a pharmacologic booster

RTV inhibits CYP3A4 in the liver, increasing PI exposure and half-life[1]

Boosting allows less frequent PI administration and lower daily dose

RTV associated with diarrhea and nausea, increased lipids, many drug–drug interactions[2]

Mea

n P

lasm

a C

on

cen

trat

ion

(S

D)

at S

tea

dy

Sta

te (

ng

/mL

)[3]

Hrs0 4 8 12 16 20 24

ATV 400 mg QD

ATV/RTV 300/100 mg QD

0

10

100

1000

10,000

Median wild-type EC90 = 14 ng/mL

1. Merry C, et al. AIDS 1997;11:F29-F33. 2. Ritonavir [package insert]. 3. Atazanavir [package insert].

Pharmacologic Boosting of ATV by RTV


Key Drug–Drug Interactions With RTV

Exposures Increase With RTV

Maraviroc Antiarrythmics Anticancer agents Anticonvulsants (some) Antidepressants (some) Beta-blockers Calcium channel blockers Colchicine Digoxin Erectile dysfunction drugs Glucocorticoids Methamphetamine Rifabutin Sedatives/hypnotics Statins (some)

Exposures Decrease With RTV

Anticonvulsants (some) Antidepressants (some) Bupropion Ethinyl estradiol Methadone Theophylline Rifampin

Ritonavir [package insert].


Cobicistat: A New Boosting Agent

Small molecule with no HIV activity

Similar from BL in fasting TC and TGs compared with RTV when boosting same agent[1]

Inhibitor of and metabolized by CYP3A4; many drug–drug interactions[2,3]

Modest, rapid increase in serum Cr due to inhibition of tubular secretion[3]

– Not associated with any change in actual GFR

– Other drugs (including certain ARVs) have similar effect[4,5]

1. Gallant JE, et al. J Infect Dis. 2013;208:32-39. 2. DHHS Guidelines. May 2014. 3. TDF/FTC/EVG/COBI [package insert]. 4. Rilpivirine [package insert]. 5. Dolutegravir [package insert].


8000

DRV/COBI FDC Bioequivalent to DRV + RTV and to DRV + COBI PK analyses in healthy subjects

DRV Concentration When DRV and COBI Administered as Single Agents

or as Coformulation[2]

DRV Concentration When Administered as DRV + RTV or as DRV/COBI Coformulation[1]

1. Kakuda TN, et al. Clin Pharmacol. 2012. Abstract O_20. 2. Kakuda TN, et al. IAS 2013. Abstract MOPE029.

HrsPla

sma

Co

nce

ntr

atio

n o

f D

RV

(n

g/m

L;

Mea

n ±

SD

)

Hrs

DRV/RTV 800/100 mg QD as single agents (n = 32)DRV/COBI 800/150 mg QD as FDC (n = 33)DRV/COBI 800/150 mg QD as FDC (n = 33)

Single agents; fed (n = 38)FDC; fed (n = 40)Single agents; fasted (n = 72)FDC; fasted (n = 74)

6000

4000

2000

0240 6 12 18

8000

6000

4000

2000

00 4 8 12 16 20 24


Key Drug–Drug Interactions With COBI

Exposure Increased With COBIAntacids

Antiarrythmics

Benzodiazepines

Beta-blockers

Calcium channel blockers

Erectile dysfunction drugs

Inhaled/injectable corticosteroids

OCPs (norgestimate)

Statins

Increase COBI Exposure

Azole antifungals

Clarithromycin

Decrease COBI Exposure

Rifabutin

Carbamazepine

Phenytoin

DHHS Adult Guidelines. May 2014.

No interaction between COBI and methadone


Creatinine Changes With Cobicistat and Ritonavir

Interpretation of changes in renal function may be problematic when using coformulations of COBI and TDF[1]

Coformulated drugs containing COBI should not be initiated in patients with estimated CrCl < 70 mL/min or used with other nephrotoxic drugs[2,3]

1. Gallant J, et al. J Infect Dis. 2013;208:32-39. 2. TDF/FTC/EVG/COBI [package insert]. 3. DHHS Guidelines. May 2014.

Ch

ang

e i

n C

reat

inin

e L

evel

, M

edia

n m

g/d

L (

IQR

)

Wks

0

-0.1

0.1

0.2

0.4

0.3

-0.2BL 12 24 36 48

COBIRTV

Boosted PIs in Treatment-Naive Patients,

Including Acute HIV Infection


Zolopa AR, et al. PLoS One. 2009;4:e5575.

ACTG 5164: Immediate vs Deferred ART for Acute OI

Total

PCP

Bacterial Infection

Other Ol

Fungal

Crypto

Mycobacterial

> 1 Ol

CD4+ < 50

CD4+ ≥ 50

0 0.25 0.5 20.08.02.51.0

54

28

11

42

12

8

8

30

39

15

282

181

41

194

52

41

18

148

196

86

# Events # Total

Log OR of Death/AIDS Progression

Favors Early ART Favors Deferred ART


Transmitted HIV Drug Resistance in MSM in 11 Jurisdictions, 2008-2011 Genotypic analysis of pol sequences of samples from 10,894 newly

diagnosed MSM pts in CDC National HIV-1 Surveillance System

Bañez Ocfemia MC, et al. CROI 2014. Abstract 579.

All cases with sequencesCases classified as recent infections (n = 3083)Cases classified as long-standing infections (n = 7810)

0

4

Transmitted Drug Resistance Mutations

1 or more

20

8

12

16

NNRTI NRTI PI

17.4

9.0

6.6

4.6

18.8

10.9

6.5

4.7

8.36.7

4.5

16.8


DHHS Guidelines: Boosted PIs in Recommended Regimens

If initiating ART in a pt with acute/early HIV before resistance test results are available, use a boosted PI plus NRTIs due to slow emergence of PI resistance and uncommon transmitted resistance

DHHS Guidelines. May 2014.

For All Pts, Regardless of BL VL or CD4+ Count

Only for Pts With Pre-ART VL < 100,000 c/mL

NNRTI EFV/TDF/FTC EFV + ABC/3TC* RPV/TDF/FTC

Boosted PI ATV/RTV + TDF/FTC DRV/RTV + TDF/FTC

ATV/RTV + ABC/3TC*

INSTI

RAL + TDF/FTC EVG/COBI/TDF/FTC DTG + ABC/3TC* DTG + TDF/FTC

*Only for pts who are HLA-B*5701 negative. Only for those with CD4+ cell counts > 200 cells/mm3.


Key Considerations in Choosing RTV-Boosted PIs in First-line ART

Advantages Disadvantages

Potent activity; low rates of transmitted PI resistance

CD4+ cell count increase generally greater than with EFV

Resistance to PI rare at virologic failure

Low risk of NRTI resistance with boosted PI failure

Options (including PIs) retained for future use

Metabolic complications due to some PIs and/or low-dose RTV

GI intolerance due to some PIs and/or low-dose RTV

Potential drug–drug interactions (CYP450)

LPV/RTV currently* only coformulated PI (others in advanced development)

Current boosted PI regimens are more pills (3) than some other options

No single-tablet regimen using current preferred PIs currently* available

*Current as of July 2014

Key Clinical Data on Atazanavir/Ritonavir and

Darunavir/Ritonavir in Treatment-Naive Patients


Atazanavir/Ritonavir Comparative Studies in Treatment-Naive Pts Randomized, noninferiority phase III studies

Primary endpoint: HIV-1 RNA < 50 c/mL at Wk 48

ART-naive ptsVL ≥ 5000 c/mL

(N = 883)

ATV/RTV + TDF/FTC (n = 440)

LPV/RTV BID* + TDF/FTC (n = 443)

*SGC until Wk 48.


(N = 1857)

ATV/RTV + ABC/3TC (n = 463)

EFV + TDF/FTC (n = 464)

CASTLE[1]

(open label)

ACTG 5202[2]

(third agent, open label; NRTIs prematurely unblinded)


EVG/COBI/TDF/FTC (n = 353)


eGFR ≥ 70 mL/min(N = 708)

GS-103[3]

(placebo controlled)

1. Molina JM, et al. Lancet. 2008;372:646-655. 2. Daar E, et al. Ann Intern Med. 2011;154:445-456. 3. De Jesus E, et al. Lancet. 2012;379:2429-2438.


EFV + ABC/3TC (n = 465)


CASTLE: ATV/RTV vs LPV/RTV in Naive Pts Through 96 Wks

ATV/RTV noninferior to LPV/RTV at Wk 48[1]; superior at Wk 96[2]

– Results consistent across BL HIV-1 RNA, CD4+ cell count, subgroups

VF in 7% of each arm by Wk 96

– 1 pt in ATV/RTV arm with major PI mutation at Wk 96 vs 0 in LPV/RTV arm; NRTI resistance in 7 vs 10, respectively

Treatment-related study d/c: 3% in each arm at Wk 96

Similar CD4+ cell count increase: +268 (ATV/RTV) vs +290 (LPV/RTV) at Wk 96

0

20

40

60

80

100

Wk 96

6874

Wk 48

7678

1. Molina JM, et al. Lancet. 2008;372:646-655. 2. Molina JM, et al. J Acquir Immune Defic Syndr. 2010;53:323-332.

Δ 1.7% (-3.8 to 7.1)

P = NS

LPV/RTV = TDF/FTC (n = 443)


Δ 6.1% (0.3 to 12.0)

P < .05

343/440

338/443

327/440

302/443n/N =


A5202: Efficacy With ATV/RTV vs EFV

Similar time to VF with ATV/RTV vs EFV, whether with TDF/FTC or ABC/3TC

Time to safety (P = .048) and tolerability (P < .001) endpoints shorter with EFV when paired with ABC/3TC but not when with TDF/FTC

Similar CD4+ count increase with ATV/RTV vs EFV when paired with ABC/3TC (+250 vs +251) but greater when paired with TDF/FTC (+252 vs +221)

Less resistance at VF with ATV/RTV vs EFV

Daar ES, et al. Ann Intern Med. 2011;154:445-456. Sax PE, et al. J Infect Dis. 2011;204:1191-1201.

EFV + TDF/FTC (57 events)ATV/RTV + TDF/FTC (57 events)EFV + ABC/3TC (72 events)ATV/RTV + ABC/3TC (83 events)

*Interim analysis showed time to VF shorter with ABC/3TC in pts with BL VL > 100,000 c/mL

0 4 16 36 8460 108 156132 180

1.0

0.8

0.6

0

0.2

0.4

8 24 48 72 96 144 168120

Wks From Randomization

Cu

mu

lati

ve P

rob

abili

ty o

f V

F

Resistance at Wk 96

Pts With Resistance, n

EFV Arms ATV/RTV Arms

NRTI 36 16

NNRTI 68 1

NRTI + NNRTI 36 0

PI resistance 0 1


EVG/COBI/TDF/FTC Noninferior to ATV/RTV + TDF/FTC Through Wk 144

EVG/COBI arm noninferior to ATV/RTV arm at Wk 48 primary endpoint[1] and through Wk 144[2,3]

– Results consistent across subgroups: BL HIV-1 RNA, CD4+ count, adherence, age, sex, race

Treatment-related study d/c: 6% in EVG/COBI arm vs 9% in ATV/RTV arm at Wk 144

VF: 8% in EVG/COBI arm vs7% in ATV/RTV arm at Wk 144

– 8 pts with resistance (NRTI + INSTI) in EVG/COBI arm vs 2 (PI only) in ATV/RTV arm at Wk 144

Similar CD4+ count increase at Wk 144: +280 (EVG/COBI) vs +293 (ATV/RTV)

1. DeJesus E, et al. Lancet. 2012;379:2429-2438. 2. Rockstroh J, et al. J Acquir Immune Defic Syndr. 2013;62:483-486. 3. Clumeck N, et al. EACS 2013. Abstract LBPS7/2.

EVG/COBI/TDF/FTC (n = 353)


Δ 3.0% (-1.9 to 7.8) Δ 1.1%

(-4.5 to 6.7)

Wk 48 Wk 144

78 75

0

20

40

60

80

10090 87

Δ 3.1% (-3.2 to 9.4)

8382

Wk 96


Lipid Changes From BL to Wk 48

This slide is an illustration only and not meant to be a cross-study comparison.

10 81111

568

23

P = .006

ATV/RTVEVG/COBI

Study 103[3]

EFV + TDF/FTCATV/RTV + TDF/FTC

P < .001

ACTG 5202[2]

P < .0001

ATV/RTVLPV/RTV

17

38

1117

2732 14

58

P < .0001

CASTLE[1]

TC LDL HDL TG

Me

dia

n C

ha

ng

e

(mg

/dL

)

0

10

20

30

40

50

60

70

TC LDL HDL TG

Me

dia

n C

ha

ng

e

(mg

/dL

)

0

10

20

30

40

50

60

70

TC LDL HDL TG

Me

dia

n C

ha

ng

e

(mg

/dL

)

0

10

20

30

40

50

60

70

22

10

40

1512

2113

24

1. Molina JM, et al. Lancet. 2008;372:646-655. 2. Daar E, et al. Ann Intern Med. 2011;154:445-456.. 3. De Jesus E, et al. Lancet. 2012;379:2429-2438.

10 82

514

813

29

EFV + ABC/3TCATV/RTV + ABC/3TC

P < .001P < .001

P < .001

P < .001

P = .002


ATV/RTV Adverse Events Summary

ATV/RTV vs LPV/RTV[1,2]:

– More rash

ATV/RTV vs EFV[3]:

– Decrease in CrCl (with TDF/FTC) vs increase with EFV; fewer CNS events

– Substudy[4]: greater loss in spine (not hip) BMD

All studies:

– More jaundice and hyperbilirubinemia

– Overall low rate (5% to 9%) of moderate to severe jaundice/scleral icterus in clinical studies of ATV/RTV[5]

1. Molina JM, et al. Lancet. 2008;372:646-655. 2. Molina JM, et al. J Acquir Immune Defic Syndr. 2010;53:323-332. 3. Daar ES, et al. Ann Intern Med. 2011;154:445-456. 4. McComsey G, et al. J Infect Dis. 2011;203:1791-1801. 5. Atazanavir [package insert].


ACTG 5202 Substudy: Loss of Bone With EFV vs ATV/RTV Initiation

Change in Spine BMD Change in Hip BMD

McComsey G, et al. J Infect Dis. 2011;203:1791-1801.

0

-5

-1

-2

-3

-4

1920 24 48 96 144

Visit Wk From Randomization

EFVATV/RTV

133125

117116

109102

10791

8681

5848

P = .035

EFVATV/RTV

0

-5

-1

-2

-3

-4

1920 24 48 96 144

Visit Wk From Randomization

EFVATV/RTV

131123

114114

107101

10590

8180

5948

P = .61

Ch

ang

e F

rom

BL

(%

)

Ch

ang

e F

rom

BL

(%

)


DRV/RTV Comparative Studies in Treatment-Naive Pts Randomized, noninferiority phase III studies

Primary endpoint: HIV-1 RNA < 50 c/mL at Wk 48


(N = 689)

DRV/RTV + TDF/FTC (n = 343)

LPV/RTV QD or BID + TDF/FTC (n = 346)

*Investigator-selected NRTI backbone: either TDF/FTC or ABC/3TC.

ARTEMIS[1,2]

(open label)

DTG + 2 NRTIs*(n = 242)

DRV/RTV + 2 NRTIs*(n = 242)ART-naive pts

VL ≥ 1000 c/mL(N = 484)

FLAMINGO[3]

(open label)

1. Ortiz R, et al. AIDS. 2008;22:1389-1397. 2. Mills A, et al. AIDS. 2009;23:1679-1688. 3. Clotet B, et al. Lancet. 2014;[Epub ahead of print].

No phase III clinical trial comparison with EFV


ARTEMIS: DRV/RTV vs LPV/RTV in Naive Pts Through 96 Weeks

DRV/RTV noninferior to LPV/RTV at Wk 48; superior at Wk 96

– Efficacy results better in DRV/RTV arm among those with BL VL > 100K (P = .023) c/mL and CD4+ < 200 (P = .009)

VF in 1% of DRV/RTV arm vs 2% of LPV/RTV by Wk 96

– No major PI mutations in either arm at Wk 96; NRTI mutations in 2 pts in DRV/RTV arm vs 5 in LPV/RTV arm

Treatment-related study d/c: 4% in DRV/RTV arm vs 9% in LPV/RTV arm at Wk 96

CD4+ count increase at Wk 96: +171 (DRV/RTV) vs +188 (LPV/RTV)

Significantly smaller mean change in TC and TG at Wk 48 with DRV/RTV

0

20

40

60

80

100

717978

84

Wk 48[1] Wk 96[2]

1. Ortiz R, et al. AIDS. 2008;22:1389-1397. 2. Mills A, et al. AIDS. 2009;23:1679-1688.

LPV/RTV + TDF/FTC (n = 346)

DRV/RTV + TDF/FTC (n = 343)

Δ 8.4% (1.9-14.8)

P < .001 noninferiorityP < .012 superiority

Δ 5.6% (-0.1 to 11.0)

P < .001 noninferiority


FLAMINGO: DTG vs DRV/RTV + 2 NRTIs in Naive Patients at Wk 48

DTG superior to DRV/RTV at Wk 48 primary efficacy endpoint

– Efficacy results better in DTG arm among pts with BL VL > 100K

VF < 1% (n = 2) in each arm at Wk 48

– No pts with resistance in either arm at Wk 48

Treatment-related study d/c: 2% in DTG arm vs 4% in DRV/RTV arm

Same CD4+ cell count increase at Wk 48: +210 cells/mm³ in each arm

Mean increase in fasting LDL-C at Wk 48 significantly lower in DTG arm than DRV/RTV arm (P < .0001)

HIV

-1 R

NA

< 5

0 c/

mL

at

Wk

48 (

%)

9083

Δ +7.1%(0.9-13.2; P = .025)

Clotet B, et al. Lancet. 2014;[Epub ahead of print].

DTG 50 mg QD + NRTIs

DRV/RTV 800/100 mg QD

+ NRTIs

217/242

200/242

0

20

40

60

80

100


DRV/RTV Adverse Events Summary

DRV/RTV vs LPV/RTV[1]

– At Wk 96, significantly more diarrhea with LPV/RTV; more rash in DRV/RTV arm (3% vs 1%, not significant)

DRV/RTV vs DTG[2]

– More diarrhea with DRV/RTV; more headache with DTG

– Small, rapid increase in serum creatinine in first 4 wks of treatment with DTG related to inhibition of tubular secretion of creatinine by DTG

1. Mills A, et al. AIDS. 2009;23:1679-1688. 2. Clotet B, et al. Lancet. 2014;[Epub ahead of print].

Key Drug–Drug Interactions With ATV/RTV and DRV/RTV


Drug–Drug Interactions With First-line Boosted PIs and Lipid-Lowering Therapy

Antiretroviral Contraindicated Titrate Dose No Dose Adjustment

ATV/RTVLovastatin

SimvastatinAtorvastatinRosuvastatin

Pitavastatin

DRV/RTVLovastatin

Simvastatin

AtorvastatinPravastatin

RosuvastatinPitavastatin



First-line Boosted PI Drug–Drug Interactions With OCPsAntiretroviral Effect on OCP Dosing Recommendation

ATV/RTV[1,2] Ethinyl estradiol AUC 19%Norgestimate AUC 85%

OCP should contain ≥ 35 mcg ethinyl estradiol

DRV/RTV[1,2] Ethinyl estradiol AUC 44%Norethindrone AUC 14%

Additional methods of contraception recommended

1. DHHS Adult Guidelines. May 2014. 2. DHHS Perinatal Guidelines. March 2014.


First-line Boosted PI Drug–Drug Interactions With Acid-Reducing Agents

ARV Antacids H2-Receptor AntagonistsProton Pump

Inhibitors

ATV/RTV

Give ATV ≥ 2 hrs before or

1 hr after antacids orbuffered medications

Give ATV/RTV simultaneously with and/or ≥ 10 hrs after the H2-receptor antagonist

If using TDF and H2-receptor antagonist in ART-experienced pts, use ATV/RTV 400/100 mg

Use dose equivalent of famotidine ≤ 40 mg BID in ART-naive pts or ≤ 20 mg BID in ART-experienced pts

PPIs should be administered at least12 hrs before ATV/RTV

PPIs not recommended in PI-experienced pts

Use dose equivalent of omeprazole ≤ 20 mg daily in PI-naive pts

DRV/RTVNo clinically relevant

interactionsNo clinically relevant

interactionsNo clinically relevant

interactions


ACTG 5257: Comparison ofATV/RTV vs RAL vs DRV/RTV

in First-line Therapy


ACTG 5257: Open-Label ATV/RTV vs RAL vs DRV/RTV in First-line ART

Primary endpoints

– VF: time to HIV-1 RNA > 1000 c/mL (at Wk 16 or before Wk 24) or > 200 c/mL (at or after Wk 24)

– TF: time to discontinuation of randomized component for toxicity

Composite endpoint: the earlier occurrence of either VF or TF in a given participant

Switch of regimens allowed for tolerabilityLandovitz R, et al. CROI 2014. Abstract 85.

ART-naive patients with HIV-1 RNA ≥ 1000 c/mL

(N = 1809)

ATV/RTV 300/100 mg QD +TDF/FTC(n = 605)

RAL 400 mg BID +TDF/FTC(n = 603)

Stratified by HIV-1 RNA < or ≥ 100,000 c/mL, participation in

metabolic substudy, CV risk

DRV/RTV 800/100 mg QD +TDF/FTC(n = 601)

Wk 96 after last patient enrolled


ACTG 5257: Primary Endpoint Analyses at Wk 96

Regimens equivalent in time to VF

Landovitz R, et al. CROI 2014. Abstract 85. Reproduced with permission.

Significantly greater incidence of treatment failure with ATV/RTV vs RAL or DRV/RTV

– In part due to high proportion of pts with hyperbilirubinemia

Considering both efficacy and tolerability, RAL superior to either boosted PI

DRV/RTV superior to ATV/RTV

Virologic Failure Tolerability Failure Composite Endpoint

Difference in 96-Wk Cumulative Incidence (97.5% CI)

0-10 10 20

ATV/RTV vs RAL3.4% (-0.7 to 7.4)

DRV/RTV vs RAL5.6% (1.3-9.9)

ATV/RTV vs DRV/RTV-2.2% (-6.7 to 2.3)

ATV/RTV vs DRV/RTV9.2% (5.5-13.0)

0-10 10 20

ATV/RTV vs RAL13% (9.4-16.0)

DRV/RTV vs RAL3.6% (1.4-5.8)

Favors RAL

Favors DRV/RTV

0-10 10 20

ATV/RTV vs RAL15% (10-20)

DRV/RTV vs RAL7.5% (3.2-12.0)

ATV/RTV vs DRV/RTV7.5% (2.3-13.0)

Favors RAL

Favors DRV/RTV

Favors RAL


89%

ACTG 5257: Virologic Efficacy

In ITT analysis with ART changes allowed (per protocol), regimens similar in virologic efficacy at Wk 96 and through Wk 144

In ITT analysis when change = failure (Snapshot), RAL superior to both boosted PIs at Wk 96 and DRV/RTV superior to ATV/RTV at Wks 96 and 144

Mean change in CD4+ count across arms– ATV/RTV (+284); RAL (+288)

DRV/RTV (+256) cells/mm3

1.0

Pro

po

rtio

n W

ith

HIV

-1 R

NA

≤ 5

0 c

/mL

0.8

0.6

0.4

0.2

0

ITT, Regardless of ART Change

0 24 48 64 80 96 120 144

1.0

0.8

0.6

0.4

0.2

0

ITT, NC = Failure (Snapshot)

RALDRV/RTVATV/RTV

Study Wk

0 24 48 64 80 96 120 144

88%

94%

63%73%80%

RALDRV/RTVATV/RTV

Landovitz R, et al. CROI 2014. Abstract 85. Reproduced with permission.


ACTG 5257: Resistance

VF with drug resistance occurred more often in patients initially assigned to RAL[1]

– 3% randomized to RAL had ≥ 1 resistance mutation and 1.8% had INSTI mutations

– 1.5% randomized to ATV/RTV and < 1% randomized to DRV/RTV developed resistance

– No major PI mutations observed

1. Landovitz R, et al. CROI 2014. Abstract 85.


ACTG 5257: Mean Change From BL in Fasting Lipids

30

20

10

00 24 48 96 144

15

10

5

0

-50 24 48 96 144

0 24 48 96 144

0 24 48 96 144

10.0

7.5

5.0

2.5

0

40

20

0

-20

Study Wk

Ch

ang

e (

mg

/dL

)

Fasting TC

Study Wk

Fasting LDL-C

Study Wk

Fasting TG

Study Wk

Fasting HDL-C

ATV/RTV RAL DRV/RTV

Ofotokun I, et al. CROI 2014. Abstract 746.

Ch

ang

e (

mg

/dL

)

Ch

ang

e (

mg

/dL

)

Ch

ang

e (

mg

/dL

)


ACTG 5257: Loss of BMD With First-line Boosted PI vs RAL All arms associated with

significant loss of BMD through Wk 96 (P < .001)

At hip and spine, similar loss of BMD in the PI arms

– Significantly greater loss in the combined PI arms than in the RAL arm

ATV/RTV RALDRV/RTVCombined PI arms

-5

-4

0

-3

-2

-1

-3.9-3.4

-3.7

-2.4

-1.8

-4.0-3.8

-3.6

P = .36

Total Hip Total Spine

P = .005

P = .42

P < .001

Brown T, et al. CROI 2014. Abstract 779LB. Reproduced with permission.


PI Resistance Rare at VF in First-line Studies of Boosted PIsStudy n PI Wk Genotypes Major PI Mutations

CASTLE[1] 440443

ATV/RTVLPV/RTV

962626

10

ACTG 5202[2] 463465

ATV/RTV 968357

10

Study 103[3] 355 ATV/RTV 144 NR 0

ARTEMIS[4] 343346

DRV/RTVLPV/RTV

963146

00

FLAMINGO[5] 242 DRV/RTV 48 NR 0

ACTG 5257[6] 605601

ATV/RTVDRV/RTV

967599

00

1. Molina JM, et al. Lancet. 2008;372:646-655. 2. Daar ES, et al. Ann Intern Med. 2011;154:445-456.3. Clumeck N, et al. EACS 2013. Abstract LBPS7/2. 4. Mills A, et al. AIDS. 2009;23:1679-1688. 5. Clotet B, et al. Lancet. 2014;[Epub ahead of print]. 6. Landovitz R, et al. CROI 2014. Abstract 85.

Among 4303 pts in these trials, only 2 pts developed major PI mutations at initial VF

Special Considerations: Boosted PIs in Pregnancy and

First Failure


Antiretroviral Agents and Pregnancy

Guideline Categorization

NRTI NNRTI PIEntry

InhibitorINSTI

Fusion Inhibitor

Preferred

ABC/3TC*TDF/FTC or

3TC ZDV/3TC‡

EFV§ LPV/RTV¶

ATV/RTV

Alternative NVP‖ DRV/RTVSQV/RTV**

RAL

Insufficient data RPV FPV/RTV MVCDTG

EVG/COBI

Not recommended‡‡

ABC/3TC/ZDVd4Tddl

ETR

IDV/RTVNFVRTVTPV

T20

DHHS Perinatal Guidelines. March 2014.

*Should not be used in pts who are HLA-B*5701 positive. TDF combinations should be used with caution in pts with renal insufficiency. ‡Most experience for use in pregnancy but potential for hematologic toxicity. §After first 8 wks of pregnancy. Preferred when potential for drug–drug interactions with PI a problem. ¶Once-daily administration not recommended for pregnant pts. ‖Use with caution in pts with CD4+ counts > 250 cells/mm3 due to potential for liver toxicity; use with caution with ABC since both associated with potential for HSR. **Baseline EKG recommended; contraindicated in pts with preexisting cardiac condition. Limited data on use in pregnancy, but may be considered when drug–drug interactions with PI regimens are a concern. ‡‡Because of toxicity, lower rates of virologic suppression or lack of data in naive pts.


Antiretroviral Pregnancy Registry: Birth Defects With First Trimester Exposure Enrolls ~ 1300 women exposed

to ART each yr (80% US)

18,488 live births with follow-up data through July 2013

– 7790 with first trimester exposure

Overall birth defect prevalence comparable to CDC population–based surveillance data: 2.9 per 100 live births vs 2.7

Commonly used PIs not associated with increased birth defect rate

Antiretroviral Pregnancy Registry. Interim Report. December 2013.


PI-Based ART and Preterm Delivery

Mma Bana (study of HAART for PMTCT, N = 530)

– PI-based HAART (ZDV/3TC + LPV/RTV) associated with 2-fold higher rate of preterm delivery than triple-NRTI HAART, but no increase in infant morbidity or mortality through 6 mos of life[1]

Retrospective US analysis

– Among 161 HIV-infected women in US with singleton pregnancies (n = 53 on PI-based ART, 84 on non–PI-based ART, 6 on no ART), no association between PI and premature birth or low birth weight[2]

1. Powis K, et al. J Infect Dis. 2011;204 :506-514. 2. Dola CP, et al. J Perinat Med. 2011;40:51-55.


ACTG 5202: Efficacy and Tolerability by Sex With EFV and ATV/RTV Of 1857 pts, 322 were women

Women on ATV/RTV arm had a higher risk of VF with either NRTI backbone

ATV/RTV and EFV did not differ significantly by sex in safety and tolerability measures

Women on ABC/3TC had a significantly higher (32%) safety risk compared with men

With TDF/FTC, the safety risk was 20% larger for women compared with men (not statistically significant)

Self-reported adherence similar between sexes

Smith K, et al. Clin Infect Dis. 2014;58:555-563.

VF(all)VF (univariate)

ATV/RTVEFV

VF (multivariate)ATV/RTVEFV

Grade 3/4 Safety (all)Grade 3/4 Safety (univariate)

ATV/RTVEFV

Tolerability (all)Tolerability (univariate)

ATV/RTVEFV

1.05 (0.70-1.58)

1.70 (1.01-2.87)0.63 (0.33-1.20)

1.72 (0.99-2.99)0.51 (0.25-1.02)1.32 (1.03-1.70)

1.44 (0.98-2.10)1.20 (0.86-1.68)0.86 (0.64-1.16)

0.85 (0.52-1.37)0.82 (0.57-1.19)

.017

.006

.035.49

.31

.92

Women vs Men P Value

Men at Higher Risk Women at Higher Risk0.17 1.00 6.00

HR (95% CI) With ABC/3TC

VF (all)VF (univariate)

ATV/RTVEFV

VF (multivariate)ATV/RTVEFV

Grade 3/4 Safety (all)Grade 3/4 Safety (univariate)

ATV/RTVEFV

Tolerability (all)Tolerability (univariate)

ATV/RTVEFV

1.74 (1.13-2.69)

2.69 (1.54-4.70)1.00 (0.49-2.05)

2.36 (1.30-4.26)0.88 (0.42-1.84)

1.20 (0.88-1.62)

1.38 (0.91-2.08)1.03 (0.66-1.61)1.11 (0.81-1.52)

1.17 (0.75-1.83)1.07 (0.68-1.67)

.028

.034

.26

.35

.51

.78

P Value

Men at Higher Risk Women at Higher Risk0.17 1.00 6.00

HR (95% CI) TDF/FTC


SECOND-Line: Boosted PI ART After First-line VF on an NNRTI-Based Regimen Randomized, multinational, open-label noninferiority phase IIIb/IV trial

Primary endpoint: HIV-1 RNA < 200 copies/mL at Wk 48

LPV/RTV + RAL (n = 270)

LPV/RTV + 2-3 NRTIs* (n = 271)

HIV-infected ptswith VF on first-line regimen of NNRTI +

2 NRTIs(N = 541)

Δ -1.8% (-4.7 to 8.3)

HIV

-1 R

NA

< 2

00 c

/mL

at

Wk

48 (

%)

83 81

223 2190

20

40

60

80

100

n =

*77% received 2 NRTIs; 23% received 3 NRTIs. Most common NRTIs: TDF, 81%; FTC/3TC, 87%; ZDV, 45%

Wk 48 Wk 96

Boyd MA, et al. Lancet. 2013;381:2091-2099.


In Pts With Isolated M184V, (3TC or FTC) + NRTI + bPI Sufficient for Suppression Retrospective analysis of pts

with M184V mutation in British Columbia HIV Drug Treatment Program, 2000-2006

Pts categorized by regimen after identification of M184V

– 3TC or FTC + NRTI + bPI (n = 48)

– 3TC or FTC + NRTI + bPI + another ART agent (n = 25)

– 3TC/FTC-sparing: 2 NRTIs + bPI ± another ART agent (n = 44)

Neither failed regimen nor subsequent regimen associated with time to HIV-1 RNA suppression

Factor Associated With Virologic Suppression

HR (95% CI)

IDU history 0.37 (0.24-0.59)

Regimen failed at M184V detection

NNRTI based Reference

bPI based 0.77 (0.42-1.41)

Other 1.37 (0.83-2.26)

Subsequent regimen

(3TC or FTC) + NRTI + bPI Reference

(3TC or FTC) + NRTI + bPI + additional active agent(s)

1.09 (0.60-1.96)

(3TC or FTC)-sparing: 2 NRTIs + bPI ± additional agents

0.61 (0.37-1.03)

≥ 95% adherence 6 mos after study start, %

2.40 (1.31-4.43)

Hull M, et al. ICAAC 2009. Abstract H-916.

Summary and Future Directions:Potential for New Coformulations


ATV/COBI + TDF/FTC Noninferior to ATV/RTV + TDF/FTC Through Wk 48 Randomized, double-blind, phase III trial in ART-naive patients

– Primary endpoint: HIV-1 RNA < 50 copies/mL at Wk 48

Gallant JE, et al. J Infect Dis. 2013;208:32-39.

ART-naive pts, HIV-1 RNA

≥ 5000 c/mL, eGFR ≥ 70

mL/min(N = 692)

TDF/FTC + ATV/COBI(n = 344)

TDF/FTC + ATV/RTV(n = 348)

Wk 48Wk 24 ATV/COBIATV/RTV

Δ -2.2% (-7.4 to 3.0)

Virologic Success*

Virologic Failure

Pat

ien

ts (

%)

85 87

293 3040

20

40

60

80

100

5.8 4.09.0 8.6

6

20 14

No Data

n = 31 30

*HIV-1 RNA < 50 c/mL as defined by FDA Snapshot algorithmDiscontinued for AE, death, or missing data.

Coformulation of ATV and COBI being considered for approval by FDA


Ongoing Studies of COBI-Boosted DRV Plus 2 NRTIs Phase IIIb study in tx-naive tx-exp’d

pts with no DRV RAMs[1]

– Primary endpoint: grade 3 or grade 4 AEs by Wk 24

– Secondary endpoints: HIV-1 RNA at Wk 24 and Wk 48

Randomized, double-blind phase II trial[2]

– Primary endpoint: HIV-1 RNA < 50 copies/mL at Wk 24

Pts with HIV-1 RNA≥ 500; naive or on stable ART for 12

wks and sensitive to 2 NRTIs with no

DRV RAMS(N = 300)

DRV + COBI + 2 NRTIs

Wk 48

1. ClinicalTrials.gov. NCT01440569. 2. ClinicalTrials.gov. NCT01565850.

ART-naive pts, HIV-1 RNA

≥ 5000 c/mL,

eGFR ≥ 70 mL/min(N = 150)

DRV/COBI/TAF/FTC QD

(n = 75)

DRV/COBI + TDF/FTC(n = 75)

Wk 48Wk 24

Wk 24

Coformulation of DRV and COBI being considered for approval by FDA


Boosted Atazanavir: Advantages and Disadvantages


Efficacy comparable to EFV at Wk 96[1]

Favorable lipid profile[2,3]

Low risk of resistance at failure[1-3]

Pill burden similar to DRV/RTV—lowest among boosted PIs

Can be given unboosted Once-daily dose requires only RTV

100 mg/day Currently being studied as

coformulated boosted PI with cobicistat[4]

Higher rates of treatment failure than DRV/RTV and RAL in ACTG 5257 due to tolerability[5]

Associated with increase in unconjugated bilirubin and scleral icterus in 4% to 9% of patients[6]

Absorption impaired with acid-reducing agents[6]

Food requirement for dosing[6]

No plans for single-tablet regimen

1. Daar ES, et al. Ann Intern Med. 2011;154:445-456. 2. Molina JM, et al. Lancet. 2008;372:646-655. 3. Molina JM, et al. J Acquir Immune Defic Syndr. 2010;53:323-332. 4. Gallant JE, et al. J Infect Dis. 2013;208:32-39. 5. Landovitz R, et al. CROI 2014. Abstract 85. 6. Atazanavir [package insert].


Boosted Darunavir: Advantages and Disadvantages


Favorable lipid profile[1,2]

Low risk of resistance at failure[1,2]

Pill burden similar to ATV/RTV—lowest among boosted PIs

Lower risk of treatment failure than ATV/RTV in ACTG 5257[3]

Once-daily dose requires only RTV 100 mg/day[5]

Currently being studied as coformulated boosted PI with cobicistat and single-tablet regimen

Rash in ~ 6% of patients; use with caution in patients with sulfa allergy[4]

Inferior to DTG in Flamingo study[5]

Cannot be given unboosted

1 Ortiz R, et al. AIDS. 2008;22:1389-1397. 2. Mills AM, et al. AIDS. 2009;23:1679-1688. 3. Landovitz R, et al. CROI 2014. Abstract 85. 4. Darunavir [package insert]. 5. Clotet B, et al. Lancet. 2014;[Epub ahead of print].


Conclusions

Boosted PIs appropriate for many ART-naive and treatment-experienced patients

Long history of clinical experience with this class

Low prevalence of transmitted resistance

High levels of virologic suppression in first-line therapy

No major PI resistance at initial VF in many clinical trials

Newer preferred PIs have improved metabolic profile

Ritonavir and cobicistat associated with many drug–drug interactions

Newer booster, cobicistat, may offer new opportunities for coformulation with a concomitant decrease in pill burden

Go Online for More Educational Content on Boosted Protease

Inhibitors!Interactive Virtual Presentation featuring streaming narration of these slides and case studies illustrating the use of boosted protease inhibitors across the treatment spectrum by expert faculty Sally Hodder, MD

clinicaloptions.com/boostedPI

http://www.clinicaloptions.com/boostedPI

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Boosted Protease Inhibitors. Current and Future Role in HIV Therapy.2014

Health & Medicine